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The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.

The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.

ObjectiveThere is an association between latitude, relative vitamin D deficiency and risk of multiple sclerosis (MS), and an association between vitamin D and disease progression. We have performed a meta-analysis with the aim of investigating the role of therapeutic vitamin D in MS.MethodsA systematic search of databases was performed to identify clinical trials assessing vitamin D in patients with relapsing–remitting MS. Studies were selected based on inclusion and exclusion criteria. Analysis was performed using RevMan 5.3 software.ResultsTwelve studies involving 950 patients were included in the final analysis. Studies were divided into four groups because of heterogeneity in study design. Studies were judged to be at low or unclear risk of bias, except in three studies, and this was confirmed by funnel plots. No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures, particularly when only placebo-controlled studies were included. Dose comparison studies showed a significant increase in annualised relapse rate (mean difference 0.15 [95%CI 0.01–0.30]) and non-significant trends of increased Expanded Disability Status Scale and gadolinium-enhancing lesions for the higher-dose arms.ConclusionThese findings suggest that vitamin D supplementation may have a therapeutic role in the treatment of MS. However, there is uncertainty with regard to the most appropriate dose, with high doses potentially being associated with worse outcomes. There remains the need for further well-performed randomised, dose-ranging, placebo-controlled trials of vitamin D in MS.

The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18–55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3–5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was −3·5 ms (17·3 vs 20·8 [95% CI −10·6 to 3·7]; 17%; p=0·33) in the ITT population, and −7·6 ms in the PP population (14·7 vs 22·2 [−15·1 to 0·0]; 34%; p=0·050) at week 24 and −6·1 ms (15·1 vs 21·2 [−12·7 to 0·5]; 29%; p=0·071) in the ITT population and −9·1 ms (13·2 vs 22·4 [−16·1 to −2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. Biogen.

The autoimmune encephalitides are a group of autoimmune conditions targeting the central nervous system and causing severe clinical symptoms including drug-resistant seizures, cognitive dysfunction and psychiatric disturbance. Although these disorders appear to be antibody mediated, the role of innate immune responses needs further clarification. Infiltrating monocytes and microglial proliferation at the site of pathology could contribute to the pathogenesis of the disease with resultant blood brain barrier dysfunction, and subsequent activation of adaptive immune response. Both innate and adaptive immune cells can produce pro-inflammatory molecules which can perpetuate ongoing neuroinflammation and drive ongoing seizure activity. Ultimately neurodegenerative changes can ensue with resultant long-term neurological sequelae that can impact on ongoing patient morbidity and quality of life, providing a potential target for future translational research.

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely measures a user’s mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (‘active tests’). Levels of mobility of study participants (‘life-space measurement’) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

There are a broad range of disease-modifying therapies (DMTs) available in relapsing-remitting multiple sclerosis (RRMS), but limited biomarkers exist to personalise DMT choice. All DMTs, including monoclonal antibodies such as rituximab and ocrelizumab, are effective in preventing relapses and preserving neurological function in MS. However, each agent harbours its own risk of therapeutic failure or adverse events. Pharmacogenetics, the study of the effects of genetic variation on therapeutic response or adverse events, could improve the precision of DMT selection. Pharmacogenetic studies of rituximab in MS patients are lacking, but pharmacogenetic markers in other rituximab-treated autoimmune conditions have been identified. This review will outline the wider implications of pharmacogenetics and the mechanisms of anti-CD20 agents in MS. We explore the non-MS rituximab literature to characterise pharmacogenetic variants that could be of prognostic relevance in those receiving rituximab, ocrelizumab or other monoclonal antibodies for MS.

BackgroundDiscontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.Objectives(1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.MethodsInclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.ResultsTime to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.ConclusionsPatients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

Background: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. Methods: MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1–3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test–retest reliability and the discriminative ability of MSReactor. Results: A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them ‘very anxious’. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. Conclusion: MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified.

Background The optimal management of migraine involves care strategies that reflect what matters most to patients. This usually involves an assessment of treatment efficacy with respect to headache reduction, safety of prescribed medications and overall patient satisfaction and/or improved quality of life. Traditionally, neurologists focus on objective measures such as monthly reductions to headache and migraine days from baseline. This is complemented with various patient reported outcome measures (PROMs) to quantify morbidity and treatment effect from the patient’s perspective. We present a review of currently available headache specific PROMs to summarise the design, key attributes, response format, recall period and length of questionnaires. Methods A literature search was conducted using OVID Medline, Embase and Cochrane Library. The search strategy involved: (satisfaction OR patient satisfaction OR efficacy OR effectiveness) AND (disability OR morbidity OR burden OR severity OR impact OR patient reported outcomes OR PROMs OR outcome measures OR MIDAS OR HIT6 OR HDI OR MSQ OR MIG-SCOG OR Eq. 5D OR WPAI OR PGIC OR quality of life or QOL) AND (migraine OR chronic migraine OR headache OR primary headache OR cephalalgia OR headache disorder). A total of 16,024 articles returned. Removal of duplicates ( n  = 111), title and abstract screening ( n  = 15,853) and subsequent full text analysis ( n  = 19), left 41 articles. Reviewer comments led to addition of further 3 articles to our review. In total, of 44 included articles there were 20 headache-specific PROMs analysed. Results and conclusion Our findings show that there is a significant lack of patient involvement in creation of headache PROMs thus there may be a gap between perceived treatment efficacy from the perspective of neurologists and that of patients. We suggest future assessment of migraine treatment efficacy considers what is important to the patient as a priority, in an effort to improve satisfaction with care.